Among the most compelling questions still left unresolved in cognitive research are 1) what are the first brain regions to degenerate in patients with early cognitive decline and b) what central nervous systems changes occur when an individual progresses from cognitive impaired to demented. A number of brain regions and brain systems degenerate in Alzheimer's disease (AD) and an understanding of the temporal sequence of these changes and the role they play in mediating specific aspects of cognitive decline is crucial. The dopaminergic mesocortical and meostriatal systems have been underappreciated in their involvement in human cognitive decline. Over the past two decades, a consensus have evolved establishing a role for dopaminergic mesocortical and meostriatal function in working memory and executive function in mammals, especially primates. The presently proposed series of experiments is founded on two fronts: 1) positive preliminary data indicating that there is a loss of dopaminergic midbrain neurons and a phenotypic down- regulation of midbrain dopaminergic neurons in individuals with midbrain neurons and a phenotypic down-regulation of midbrain dopaminergic neurons in individuals with AD; 2) our laboratories unique ability to specifically lesion dopaminergic mesocortical or meostriatal systems in young and aged monkeys in an effort to elucidate mechanism by which cognitive decline takes place in primates. Toward this end, the present proposal has four Specific Aims that test the hypothesis that alterations in dopaminergic mesocortical systems are associated with changes seen in early cognitive decline such as those patients exhibiting mild cognitive impairment (MCI) and that further exacerbation of dopaminergic mesocortical and meostriatal pathology. To test these hypotheses, Specific Aims 1 and 2 will employ detailed morphological and biochemical analyses to determine the integrity of these midbrain dopaminergic systems in individuals with normal cognitive impairment, MCI and AD. These morphologic and biochemical indices of dopaminergic function will also be correlated with performance by these individuals on specific tasks of working memory. The final two Specific Aims will employ young and aged monkeys to further assess the relationship between dopaminergic function and cognitive performance. We will also use aged monkeys to model the cognitive decline seen in MCI individuals and then create lesions of the dopaminergic mesocortical system or the dopaminergic meso-anteriostriatal system to determine whether loss of one of these systems in isolation is sufficient of transition aged monkeys to a state of exacerbated cognitive decline, modeling the transition of humans from MCI to AD.